The present invention is concerned generally with myocardial infarctions of the heart and the damage caused to the heart of a living mammalian subject by such infarctions; and is particularly directed to methods and means for improving cardiac function and the potential repair of infarcted areas of the heart after the occurence of a myocardial infarction.
Myocardial infarction (MI) is a life-threatening event that may cause cardiac sudden death and heart failure. Despite considerable advances in the diagnosis and treatment of heart disease, cardiac dysfunction after MI is still the major worldwide cardiovascular disorder that is increasing in incidence, prevalence, and overall mortality1. After acute myocardial infarction, the damaged cardiomyocytes are gradually replaced by fibrotic non-contractile tissue. The developing ventricular dysfunction is primarily due to a massive loss of cardiomyocytes. It is widely accepted that adult cardiomyocytes have little regenerative capability. Therefore, the loss of cardiac myocytes after MI is irreversible. Finding new effective approaches to improve cardiac dysfunction after MI remains a major therapeutic challenge.
Cell transplantation has emerged as a potentially new approach of repairing damaged myocardium for recent several years. Transplanted cardiomyocytes have been shown to survive, proliferate, and connect with the host myocardium in murine models2. Li and his coworkers3,4 demonstrated that transplanted fetal cardiomyocytes could form new cardiac tissue within the myocardial scar induced by cryoinjury and improve heart function, but the transplanted allogenic cells survived for only a short period in the recipient heart due to immunorejection5. Bishop et al.6 reported that the embryonic myocardium of rats can be implanted and cultured in oculo and demonstrated that the engrafted embryonic cardiomyocytes proliferated and differentiated in a recent review, Heschler et al.7 pointed out that pluripotent embryonic stem (ES) cells cultivated within embryonic bodies reproduce highly specialized phenotypes of the cardiac tissue. Most of the biological and pharmacological process of cardiac-specific ion currents are expressed in cardiomyocytes developed in vitro from pluripotent ES cells, which were similar to those previously described in adult cardiomyocytes or neonatal mammalian heart cells7,8 However the significance of ES cell transplantation in postinfarcted failing hearts remains to be examined.
Several studies have demonstrated the feasibility of engrafting exogenously supplied cells into host myocardium, including fetal cardiomyocytes2 derived from artial tumor (ATI)15, satellite cells16, or bone marrow cells17. These engrafted cells have been histologically identified in normal myocardium up to 4 months after transplantation15 Gap junctions have been found between the engrafted fetal cardiomyocytes and the host myocardium2, thereby raising the possibility of electrical-contraction coupling between transplanted cells and the host tissue. Recently, myocyte transplantation has been extended into ischemically damaged myocardium with coronary artery occlusion in rats0.8, or with cryoinjury in rats3,4 and dogs16.
Nevertheless, despite all these research efforts and reported investigations, very little progress has been made to date in methods and cellular materials which might directly or markedly improve cardiac function in the living host after the occurrence of a myocardial infarction; or might serve as a cell transplantation therapeutic technique for effecting at least a partial repair of the infarcted area of the myocardium; or might offer a potential long-term improvement of the damaged heat tissue in the afflicted host subject. Were such an effective methodology to be generated and empirically demonstrated, such a development would be regarded as a major advance and unforeseen event by physicians and surgeons working in the field of cardiology.
The present invention provides a method for improving cardiac function in a living mammalian subject after the occurrence of a myocardial infarct within the heart tissue, said method comprising the steps of:
obtaining a plurality of undifferentiated mammalian embryonic stem cells then maintained in a culture media suitable for subsequent initiation of cell differentiation;
introducing said cultured mammalian embryonic stem cells to at least a portion of the previously infarcted area of the heart tissue in the living subject; and
allowing said introduced mammalian embryonic stem cells to differentiate in-situ as viable cells situated within the previously infarcted area of the heart tissue, whereby the cardiac function of the heart in the living subject becomes markedly improved.